Historically the term frailty has been interchanged with co-morbidity, disability, and extreme old age. In the last decade Geriatrics researchers have developed, refined, and validated a concept of frailty. It is a syndrome that at its core involves a clinical state of vulnerability to stressors thought to be due to "multisystem dysregulation". The criteria of measuring a Frailty Index include: unintentional weight loss, exhaustion, loss of strength, slow walking speed, and low level of activity. The Frailty Index is a validated instrument that classifies older adults into three defined categories: robust (healthy), pre-frail, and frail. There is a clear association between frailty, increased mortality, and declines in other performance measures in several ethnic populations in the U.S. and Europe. Frailty is a common condition in community dwelling elderly adults with a prevalence 7-10 % among those age 65, 25% in individuals over age 80, and even higher in individuals in long-term care facilities. Pre-frailty is an intermediate category between robust and frail, and predicts progress to frailty. The incidence of pre-frailty is even more common than frailty. The current level of understanding of the immune system in older individuals is based almost exclusively on age. There have been very few immunologic studies that have addressed any relationship between immunologic dysfunction and frailty. Older individuals, especially ones with greater debility and frailty, are largely excluded from clinical trials and are significantly understudied. It has been established that increasing age leads to both immunologic dysfunction and poor responses to vaccination. The overall hypothesis that frailty and age predict immunologic and vaccination failure in older adults. However, frailty will be a stronger predictor than age of immunologic and vaccination failure. This hypothesis will be addressed with the following specific Aims: Aim 1. To determine the relationship between frailty and immunologic dysfunction in older adults. The hypothesis is that certain immune defects will be more strongly associated with frailty than age. To test this hypothesis, a panel of established immunologic tests to measure the function of T cells, antigen presenting cells (APC), and B cells in older adults that are robust (healthy), pre-frail, and frail as measured by a Frailty Index will be used. Subjects will be enrolled in the age groups of 65-74, 75-84 and over 85 years to allow a direct comparison of specific aspects of immunologic function between frailty and age. The studies in the immunologic panel will focus on T cell, APC, and B cell phenotypes and functions that are critical for a successful vaccine response. We predict that the T cell compartment will demonstrate the greatest dysfunction with advancing frailty and age. Aim 2. To determine the relationship between frailty status and poor influenza vaccine response in older adults. We hypothesize that vaccine failure correlates closely with frailty as well as age. To test this hypothesis, we will vaccinate the same frailty and age matched subjects in Aim 1 with trivalent inactivated influenza vaccine and measure antibody responses after 4-12 weeks. Aim 3. To determine which specific immunologic dysfunction(s) mediate the relationship between frailty and poor influenza vaccine responses. The specific immune defects observed (Aim 1) that mediate the reduced influenza-specific antibody titers that result from vaccination (Aim 2) will be determined in the frailty groups with age as a covariable. Taking into account the influence of frailty and age, we will determine which immune functions most likely are the mechanism(s) of the poor vaccine response. Aim 4. To develop a clinical algorithm to predict the efficacy of influenza vaccination based on categories of frailty and age. We will use the 3 frailty categories and 3 age groups to develop a clinically useful algorithm to predict influenza vaccine success and failure. This tool could guide use of prophylaxis and alternative protective strategies clinically. PUBLIC HEALTH RELEVANCE: The proposed studies are highly significant to the Veteran population. Over 9 million veterans comprising of 39% of patients in the VA system are 65 or older. Around 90% of influenza-related deaths occurred among adults aged >65 years in the United Sates. The risk of mortality due to influenza is increased in older individuals in spite of an aggressive vaccination campaign. Identification and validation of specific biomarkers of protective vaccination in older adults with and without frailty and the algorithm of estimation of protective efficacy could help determine who might require additional protective measures in the setting of an influenza outbreak. New vaccines and/or administration schedules need to be developed to tailor to the needs of the aging immune system. In order to achieve this, it is necessary to have an increased understanding of the immune dysfunction in older veterans to identify what specific defects must be overcome.